Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/133420
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Type: Journal article
Title: The effect of dihydroceramide desaturase 1 inhibition on endothelial impairment induced by indoxyl sulfate
Author: Savira, F.
Kompa, A.R.
Kelly, D.J.
Magaye, R.
Xiong, X.
Huang, L.
Liew, D.
Reid, C.
Kaye, D.
Scullino, C.V.
Pitson, S.M.
Flynn, B.L.
Wang, B.H.
Citation: Vascular Pharmacology, 2021; 141:106923-106923
Publisher: Elsevier BV
Issue Date: 2021
ISSN: 1537-1891
1879-3649
Statement of
Responsibility: 
Feby Savira, Andrew R. Kompa, Darren J. Kelly, Ruth Magaye, Xin Xiong, Li Huang, Danny Liew, Christopher Reid, David Kaye, Carmen V. Scullino, Stuart M. Pitson, Bernard L. Flynn, Bing H. Wang
Abstract: Protein-bound uremic toxins (PBUTs) have adverse effects on vascular function, which is imperative in the progression of cardiovascular and renal diseases. The role of sphingolipids in PBUT-mediated vasculo-endothelial pathophysiology is unclear. This study assessed the therapeutic potential of dihydroceramide desaturase 1 (Des1) inhibition, the last enzyme involved in de novo ceramide synthesis, to mitigate the vascular effects of the PBUT indoxyl sulfate (IS). Rat aortic rings were isolated and vascular reactivity was assessed in organ bath experiments followed by immunohistochemical analyses. Furthermore, cultured human aortic endothelial cells were assessed for phenotypic and mechanistic changes. Inhibition of Des1 by a selective inhibitor CIN038 (0.1 to 0.3 μM) improved IS-induced impairment of vasorelaxation and modulated immunoreactivity of oxidative stress markers. Des1 inhibition also reversed IS-induced reduction in endothelial cell migration (1.0 μM) by promoting the expression of angiogenic cytokines and reducing inflammatory and oxidative stress markers. These effects were associated with a reduction of TIMP1 and the restoration of Akt phosphorylation. In conclusion, Des1 inhibition improved vascular relaxation and endothelial cell migration impaired by IS overload. Therefore, Des1 may be a suitable intracellular target to mitigate PBUT-induced adverse vascular effects.
Keywords: Dihydroceramide desaturase 1
Endothelium
Vasorelaxation
Wound healing
Indoxyl sulfate
Rights: © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.vph.2021.106923
Grant ID: http://purl.org/au-research/grants/nhmrc/1092642
http://purl.org/au-research/grants/nhmrc/1087355
Appears in Collections:Medicine publications

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